A 42-year-old man with fatigue, no fever, night sweats, or weight loss, normal physical examination, marked leukocytosis with lymphocytosis and mild thrombocytopenia—what is the most likely diagnosis?

Chronic Lymphocytic Leukemia (CLL)

Based on the marked leukocytosis (WBC 85,000/µL) with lymphocytosis (28% = ~23,800 lymphocytes/µL), mild thrombocytopenia (100,000/µL), and absence of fever, night sweats, or weight loss in a 42-year-old man, chronic lymphocytic leukemia is the most likely diagnosis.

Diagnostic Rationale

Meeting CLL Diagnostic Criteria

The patient fulfills the essential diagnostic criteria for CLL:

• Absolute lymphocyte count >5,000/µL: With 28% lymphocytes and WBC of 85,000/µL, the absolute lymphocyte count is approximately 23,800/µL, well exceeding the required threshold of ≥5,000/µL (≥5 × 10⁹/L) for CLL diagnosis 1, 2.

• Age and presentation: While the median age at CLL diagnosis is 72 years, approximately 10% of patients are younger than 55 years, making this 42-year-old patient's age compatible with CLL 1.

• Asymptomatic presentation: Approximately 70-80% of CLL patients are asymptomatic at diagnosis, consistent with this patient's presentation of isolated fatigue without fever, night sweats, weight loss, or lymphadenopathy 3.

Excluding Alternative Diagnoses

Factor V Leiden and Hemolytic Anemia are excluded by:

• Normal reticulocyte count (1.2%) rules out active hemolysis 1
• Normal hematocrit (45%) and hemoglobin (15 g/dL) exclude anemia 1
• Factor V Leiden causes thrombosis, not leukocytosis

Immune Thrombocytopenic Purpura (ITP) is unlikely because:

• ITP presents with isolated thrombocytopenia without leukocytosis
• The platelet count of 100,000/µL represents only mild thrombocytopenia, which can occur in CLL due to marrow infiltration or autoimmune mechanisms 1

Disseminated Intravascular Coagulation (DIC) is excluded by:

• Absence of bleeding manifestations
• Normal metabolic panel (would expect abnormal liver function, elevated creatinine in DIC)
• Lack of acute illness or sepsis

Required Confirmatory Testing

To establish the definitive diagnosis of CLL, the following must be performed:

Essential Immediate Tests

• Flow cytometry of peripheral blood to confirm B-cell clonality and demonstrate the characteristic CLL immunophenotype: CD5+, CD19+, CD20+ (dim), CD23+, surface immunoglobulin (dim), CD79b (low) 1, 2.

• Peripheral blood smear review to identify small, mature lymphocytes with narrow cytoplasm borders, dense nuclei lacking nucleoli, and partially aggregated chromatin; presence of smudge cells (Gumprecht shadows) is characteristic 1.

Important Differential Diagnosis Consideration

Mantle cell lymphoma must be excluded because it also presents with CD5+ B-cells but has distinct features:

• Mantle cell lymphoma typically does not express CD23 (unlike CLL which is CD23+) 1
• If CD23 expression is present or atypical, perform cyclin D1 immunohistochemistry or FISH for t(11;14) translocation to definitively exclude mantle cell lymphoma 1

Additional Recommended Workup

Before any treatment consideration:

• Physical examination with careful palpation of all lymph node areas, spleen, and liver to assess for organomegaly 1, 2

• Laboratory studies: LDH, bilirubin, direct antiglobulin test (DAT), serum immunoglobulins 1

• FISH analysis for cytogenetic abnormalities, particularly del(17p) and del(11q), which have prognostic and therapeutic implications 1, 2

• Bone marrow biopsy is not required for diagnosis but is recommended before initiating therapy to evaluate cytopenias 1, 2

Clinical Staging and Management

Staging Assessment

Apply either Binet (Europe) or Rai (United States) staging system based on physical examination findings and blood counts 1, 4:

Rai Staging:

• Stage 0: Lymphocytosis only
• Stage I-II: Lymphocytosis + lymphadenopathy/organomegaly (intermediate risk)
• Stage III-IV: Lymphocytosis + anemia or thrombocytopenia (high risk)

Binet Staging:

• Stage A: <3 lymphoid areas involved, no anemia/thrombocytopenia
• Stage B: ≥3 lymphoid areas involved
• Stage C: Anemia (Hb <10 g/dL) or thrombocytopenia (<100,000/µL)

Treatment Decision

This patient should NOT receive immediate treatment based on current guidelines 1, 4:

• The absolute lymphocyte count alone is never an indication for treatment in CLL, as leukostasis symptoms rarely occur even with very high counts 1, 4

• Treatment is indicated only when patients demonstrate active disease with at least one of the following 1:

  • Progressive marrow failure (worsening anemia/thrombocytopenia)
  • Massive splenomegaly (≥6 cm below left costal margin) or progressive/symptomatic splenomegaly
  • Massive lymphadenopathy (≥10 cm longest diameter) or progressive/symptomatic lymphadenopathy
  • Progressive lymphocytosis with >50% increase over 2 months or lymphocyte doubling time <6 months
  • Autoimmune cytopenias poorly responsive to corticosteroids
  • Constitutional symptoms (≥10% weight loss in 6 months, significant fatigue, fever >38°C for ≥2 weeks, night sweats >1 month)

• Watch-and-wait strategy with monitoring every 3 months is the standard approach for early-stage, asymptomatic CLL 1, 4.

Common Pitfalls to Avoid

• Do not initiate treatment based solely on elevated WBC count: The marked leukocytosis (85,000/µL) may appear alarming, but CLL patients tolerate very high lymphocyte counts without leukostasis complications, unlike acute leukemias 1, 4.

• Do not overlook mantle cell lymphoma: Always exclude this aggressive CD5+ lymphoma through CD23 expression analysis and, if needed, cyclin D1/t(11;14) testing, as it requires immediate treatment unlike early-stage CLL 1.

• Do not assume thrombocytopenia requires treatment: The platelet count of 100,000/µL is only mildly decreased and may remain stable for years without intervention 1.

• Confirm diagnosis before labeling as CLL: Flow cytometry is mandatory to establish clonality and characteristic immunophenotype; morphology alone is insufficient 1, 2.